Differential Expression of UBE2C and ASCL1 in Neuroendocrine Carcinoma and Adenocarcinoma of the Prostate in Xenograft Models and Human Samples.
Vassiliki Tzelepi, Sankar Maity, Jiexin Zhang, Maria Karlou, Shoudan Liang, Anh Hoang, Jing-Fang Lu, Brittany Kleb, Eleni Efstathiou, Nora Navone, Ana Aparicio, Patricia Troncoso. UT MD Anderson Cancer Center, Houston, TX
Background: Neuroendocrine carcinoma (NECa) of the prostate can emerge either de novo or as castrate-resistant progression of a typical acinar adenocarcinoma (AdCa) and has an aggressive clinical course. We used xenograft models obtained from castrate-resistant primary prostate carcinomas to gain an understanding of the pathways implicated in the emergence of NECa.
Design: Xenograft models with features of typical AdCa (n=3) and NECa (n=4) were subjected to gene-expression profiling using Affymetrix HGU133 Plus 2.0. One-way ANOVA was applied to identify differentially expressed probes (DEPs). The Web-based Gene Ontology (GO) Tree Machine was used to examine GO hierarchies. Selected genes were validated by quantitative real-time PCR (qRT-PCR) and immunohistochemistry in the xenografts, their respective donor tumors and a tissue microarray (TMA) containing cores from prostatectomy specimens with AdCa (n=42) and NECa (n=10).
Results: Unsupervised hierarchical clustering of the raw data classified the xenografts according to morphology. Using FDR 0.05, we identified 140 DEPs (0.3%) between the two groups. GO analysis on these DEPs revealed significant enrichment in the “M phase of mitotic cell cycle” biologic process subtree (adjP=7.04e-08). Among them, UBE2C, a member of the anaphase-promoting complex (APC), was confirmed to be up-regulated, relative to AdCa, in NECa xenografts by both qRT-PCR (p=0.036) and immunohistochemistry (p<0.001). The APC is associated with increased expression of basic helix-loop-helix (bHLH) transcription factors; thus, we further examined the expression of ASCL1, a member of the bHLH family and a master regulator of neuronal differentiation. Expression of ASCL1 correlated with expression of UBE2C (p=0.013) and was higher in NECa than in AdCa xenografts (p<0.001). Up-regulated expression of both UBE2C and ASCL1 in NECa relative to that in AdCa was also found in the TMA of human samples (p<0.001), thus confirming preclinical findings.
Conclusions: Both UBE2C and ASCL1 are candidate biomarkers of prostatic NECa. Their up-regulated expression noted in xenograft models and, more importantly, in human samples of prostatic NECa, relative to that in AdCa, provides correlative evidence of a possible role in the emergence of the neuroendocrine phenotype of the disease in a subset of patients and implicates them as candidate therapeutic targets. Moreover, a mechanistic link between them is suggested by their correlation in NECa. Further elucidation of the role of ASCL1 and UBE2C in the pathogenesis of prostatic NECa is warranted.
Category: Genitourinary (including renal tumors)
Monday, February 28, 2011 1:00 PM
Poster Session II # 141, Monday Afternoon